Research reportDopaminergic modulation of impulsive decision making in the rat insular cortex
Introduction
Intolerance to delay of gratification, oftentimes referred to as impulsive decision making, is a prominent feature of several psychiatric disorders such as attention-deficit/hyperactivity disorder [1] and substance use disorders [2]. Accumulating evidence originating from delay discounting paradigms has stressed the importance of dopamine transmission in these processes. In these paradigms, which have been developed for both humans and laboratory animals, impulsive decisions are operationalized as the preference for smaller-immediate over delayed-larger rewards when subjects are given the choice between both options [3].
For example, in healthy volunteers, treatment with the dopamine precursor l-dopa was found to promote choice for the sooner-smaller reward over larger-delayed reward [4]. In contrast, opposite findings have also been reported and increasing dopamine transmission in healthy volunteers via acute challenges with the psychostimulant and indirect dopamine agonist d-amphetamine [5] or the catechol-O-methyl transferase (COMT) inhibitor tolcapone [6] increased preference for the larger-delayed reward. These observations in humans are paralleled by preclinical studies in rats indicating that d-amphetamine promotes choice for the larger-delayed reward [7], [8], [9], whereas opposite effects of d-amphetamine on delay-discounting have also been found [10], [11], [12]. In addition, neurochemical and electrochemical studies in rats have indicated that performance in delay discounting paradigms is associated with increments in dopamine efflux in the brain [13], [14]. Together, the findings in humans and rats strongly point toward dopaminergic modulation of impulsive decision making, yet the direction seems variable and might perhaps be explained by, for instance, differences in trait impulsivity [15], altered dopaminergic tone through COMT polymorphisms [16], or interactions with other neurotransmitter systems such as serotonin [15], [17]. In terms of contributions of dopamine receptor subtypes, both dopamine D1-like and dopamine D2-like receptors have been implicated in impulsive decision making [7], [8].
Neuroimaging studies in humans have yielded further insights into the neural correlates of impulsive decision making and revealed increased activation patterns in the prefrontal cortex, including orbitofrontal cortex, insular cortex, as well as the ventral striatum when subjects engage in delay-discounting paradigms [18], [19], [20], [21], [22], [23]. Complementary to these neuroimaging data are the effects of excitotoxic lesions of similar brain regions in rats, including the ventral striatum and subregions of the orbitofrontal cortex, which were found to modulate impulsive decision making [24], [25], [26], [27], [28]. Based on such findings it has been postulated that the brain differentially codes smaller-immediate versus larger-delayed rewards, with areas such as the lateral orbitofrontal cortex and ventral striatum encoding immediate reward and more lateral prefrontal cortical areas including the insular cortex encoding delayed reward. Indeed, evidence from electrophysiological recordings in these aformentioned brain regions fits with this notion [29], [30], [31], [32], [33].
Functionally, the insular cortex has been postulated to play a key role in maintaining homeostasis by monitoring and integrating interoceptive visceral and somatic feelings and translating these to conscious emotional perceptions [34], [35]. Based on functional properties and relaying and processing information in a posterior to anterior manner, the insular cortex is divided into three main compartments, namely the posterior granular, dysgranular and anterior agranular insular cortex. In the rat brain, tract-tracing studies have demonstrated that each of these compartments has segregated reciprocal connections with other brain regions. The posterior granular and dysgranular insular cortices are primarily interconnected with visceral thalamic relay nuclei [36] and as such functionally implicated in monitoring and integrating interoceptive stimuli. The agranular insular cortex is largely interconnected with limbic structures including the medial prefrontal cortex, the amygdala and ventral striatum [36], [37]. Thus, the integration and translation of interoceptive stimuli to emotional feelings and behavioral actions seems to be coded in the agranular insular cortex. Moreover, the rat agranular insular cortex is highly innervated in terms of dopaminergic fibers [38] and the insular cortex (including the agranular insula) contains higher densities of dopamine D1-like receptors compared to dopamine D2-like receptors across species [39], [40], [41].
Taken together, the purpose of the present study was to examine the importance of dopamine signaling – and preferential involvement of dopamine D1-like over dopamine D2-like receptors – in the agranular insular cortex in impulsive decision making. To this aim, rats were trained in a delay discounting paradigm and subsequently received micro-infusions of the dopamine D1-like receptor antagonist SCH23390 or dopamine D2-like receptor antagonist eticlopride in the agranular insular cortex.
Section snippets
Subjects
Sixteen male Wistar rats were obtained from Harlan CPB (Horst, The Netherlands). At the start of the experiments animals weighed approximately 250 g, and were housed two per cage in macrolon cages (42.5 cm × 26.6 cm × 18.5 cm; length × width × height) under a reversed 12 h light/dark cycle (lights on at 7.00 p.m.) at controlled room temperature (21 ± 2 °C) and relative humidity of 60 ± 15%. Animals were maintained at approximately 90% of their free-feeding weight, starting one week prior to the beginning of the
Histological verification of cannulae placement
Following histological analyses, correct placement of the cannulae in the insular cortex was verified for all animals. In particular, infusion sites were located in the dorsal and ventral parts of the agranular insular cortex (Fig. 1). Two animals were excluded from all analyses because infusion sites were positioned outside the borders of the agranular insular cortex. Furthermore, one animal died during the surgical procedure and was therefore excluded from the analyses. Therefore, in total n =
Discussion
To the best of our knowledge, this study is the first to demonstrate functional involvement of dopamine signaling in impulsive decision making in the rodent agranular insular cortex. We found that micro-infusions of the dopamine D1 receptor antagonist SCH23390 at a dose of 1 μg/side and not dopamine D2 receptor antagonist eticlopride into the agranular insular cortex in rats promoted choice for the smaller-immediate over larger-delayed reward in a delay-discounting task. As such the present data
Conflict of interest
The authors have no conflicts of interest to disclose.
References (68)
Causal models of attention-deficit/hyperactivity disorder: from common simple deficits to multiple developmental pathways
Biol Psychiatry
(2005)- et al.
Acute administration of d-amphetamine decreases impulsivity in healthy volunteers
Neuropsychopharmacology
(2002) - et al.
Critical involvement of dopaminergic neurotransmission in impulsive decision making
Biol Psychiatry
(2006) - et al.
Endocannabinoids promote cocaine-induced impulsivity and its rapid dopaminergic correlates
Biol Psychiatry
(2014) - et al.
Rats with different profiles of impulsive choice behavior exhibit differences in responses to caffeine and d-amphetamine and in medial prefrontal cortex 5-HT utilization
Behav Brain Res
(2008) - et al.
Decision making, impulsivity and time perception
Trends Cogn Sci
(2008) - et al.
Prefrontal coding of temporally discounted values during intertemporal choice
Neuron
(2008) - et al.
D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain
J Chem Neuroanat
(2001) Updating dopamine reward signals
Curr Opin Neurobiol
(2013)- et al.
D(1) receptors in prefrontal cells and circuits
Brain Res Brain Res Rev
(2000)
Remember the future: working memory training decreased delay discounting among stimulant addicts
Biol Psychiatry
The role of impulsivity in relapse vulnerability
Curr Opin Neurobiol
Granular insular cortex inactivation as a novel therapeutic strategy for nicotine addiction
Biol Psychiatry
Role of insular cortex D1 and D2 dopamine receptors in nicotine self-administration in rats
Behav Brain Res
Impulsive choice and impulsive action predict vulnerability to distinct stages of nicotine seeking in rats
Biol Psychiatry
Behavioral impulsivity predicts treatment outcome in a smoking cessation program for adolescent smokers
Drug Alcohol Depend
Delayed reward discounting predicts treatment response for heavy drinkers receiving smoking cessation treatment
Drug Alcohol Depend
Impulsivity, compulsivity and top-down cognitive control
Neuron
The neuropharmacology of impulsivity
Trends Pharmacol Sci
Impulsivity as a determinant and consequence of drug use: a review of underlying processes
Addict Biol
A delay-discounting primer
Dopamine, time, and impulsivity in humans
J Neurosci
Dopamine, corticostriatal connectivity, and intertemporal choice
J Neurosci
Effects of dopaminergic drugs on delayed reward as a measure of impulsive behavior in rats
Psychopharmacology (Berl)
Global 5-HT depletion attenuates the ability of amphetamine to decrease impulsive choice on a delay-discounting task in rats
Psychopharmacology (Berl)
The effects of d-amphetamine, chlordiazepoxide, alpha-flupenthixol and behavioural manipulations on choice of signalled and unsignalled delayed reinforcement in rats
Psychopharmacology (Berl)
The pharmacology of impulsive behaviour in rats: the effects of drugs on response choice with varying delays of reinforcement
Psychopharmacology (Berl)
Effects of variable training, signaled and unsignaled delays, and d-amphetamine on delay-discounting functions
Behav Pharmacol
Double dissociation between serotonergic and dopaminergic modulation of medial prefrontal and orbitofrontal cortex during a test of impulsive choice
Cereb Cortex
Effects of acute dopamine precusor depletion on immediate reward selection bias and working memory depend on catechol-O-methyltransferase genotype
J Cogn Neurosci
Interactions between serotonin and dopamine in the control of impulsive choice in rats: therapeutic implications for impulse control disorders
Neuropsychopharmacology
Congruence of BOLD response across intertemporal choice conditions: fictive and real money gains and losses
J Neurosci
Separate neural systems value immediate and delayed monetary rewards
Science
Time discounting for primary rewards
J Neurosci
Cited by (22)
Still a “hidden island”? The rodent insular cortex in drug seeking, reward, and risk
2023, Neuroscience and Biobehavioral ReviewsBetter living through understanding the insula: Why subregions can make all the difference
2021, NeuropharmacologyEffects of d-amphetamine and MK-801 on impulsive choice: Modulation by schedule of reinforcement and delay length
2019, Behavioural Brain ResearchCitation Excerpt :Elucidating the neurochemical underpinnings of impulsive choice is important as we can identify ways to treat those that have disorders characterized by excessive impulsivity (e.g., attention-deficit/hyperactivity disorder, substance use disorders). To this end, the contribution of the dopaminergic system to delay discounting has been heavily studied [1–21], although the glutamatergic system has received considerable attention during the past few years [4,19,22–30]. The neurochemical basis of impulsive choice has often been examined using delay-discounting procedures.
An insular view of the social decision-making network
2019, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Consistently, in a conditioned place preference test, rats favored the maze compartment in which they received electrical stimulation of IC (Hurtado and Puerto, 2018), and unilateral stimulation of pIC was sufficient to induce the conditioned place preference (García et al., 2013). Pattij et al. (2014) demonstrated that pharmacological blockade of IC dopamine receptors impaired performance in a delay-discounting task. In a rat gambling task, infusion of methamphetamine to IC caused rats to opt for a high-risk, high-reward option (Mizoguchi et al., 2015).
Risky decision-making is associated with impulsive action and sensitivity to first-time nicotine exposure
2019, Behavioural Brain ResearchCitation Excerpt :Elevated risk-taking in the RDT has been shown to predict greater D1 receptor expression in the insular cortex [5]. Conversely, D1 receptors in this region appear to be associated with reduced impulsive choice, as their blockade induces impulsivity in delay discounting [58]. Habit formation, measured here via reinforcer devaluation, did not differ as a function of risk-taking phenotype.
Preclinical models and neurocircuitry of gambling and impulsive behavior
2017, Current Opinion in Behavioral SciencesCitation Excerpt :Lesions to the anterior insula also decreased impulsivity on the 5CSRT, but only in animals that make high levels of such premature responses at baseline [44••]. Although the effects of lesions or inactivations of insular regions on performance of the DDT have yet to be reported, to our knowledge, direct infusion of a dopamine D1 receptor antagonist into this region dramatically increased impulsive choice [45], suggesting this region similarly contributes to this form of impulsivity. Table 1 provides a simple summary of the results of preclinical investigations into the relative roles of the six different brain regions in different aspects of impulsive and gambling-like behaviors considered here.